Role of p38 MAPK in the Microglial-Mediated Alzheimer's Disease Tau Pathology
Normally, nerve cells treated with cell culture media derived from cultured microglia (immune cells in the brain) causes p38 MAPK activation and tau hyperphosphorylation, simulating what happens in an Alzheimer’s brain. Drs. Bhaskar’ and Lamb’s team has observed that treating these nerve cells in culture with two different types of p38 MAPK inhibitors (called Inhibitor #1 and Inhibitor #2) completely blocked the p38 MAPK activation and significantly reduced tau hyperphosphorylation. Notably, these inhibitors showed maximum effect in blocking tau phosphorylation around 90 minutes after adding microglial culture media. In the second set of studies, the team performed dose-response analysis, where neurons were treated with different concentrations of p38 MAPK inhibitors prior to adding the microglial culture media. The results suggest that maximum p38 MAPK inhibition occurred at a concentration of 0.02 µM for Inhibitor #1 and was higher for Inhibitor #2, suggesting that the former inhibitor is more potent than the latter. Finally, the team gave the two inhibitors by mouth for 14 days to aged (18 months of age or older) hTau mice (3-6 animals per group) with advanced stages of tangle pathology, similar to those that occur in human Alzheimer’s disease. Mice treated with either drug showed marked decrease in p38 MAPK activation and significant reduction in tau phosphorylation. Notably, Inhibitor #1 displayed higher efficacy than Inhibitor #2. Together, the preliminary results suggest that inhibiting p38 MAPK activation reduces tau phosphorylation both in cell culture and in animal model of tauopathy. Drs. Bhaskar’ and Lamb’s team is currently studying whether this inhibition of p38 MAPK and reduced tau pathology translates into improved cognitive function in the hTau mice.
First published on: July 6, 2011
Last modified on: June 1, 2011